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    Clinical Trial Results:
    A randomized open-label study to compare safety and efficacy of vildagliptin versus NPH insulin add-on to glimepiride in patients with type 2 diabetes mellitus that do not reach adequate glycemic control on their current sulfonylurea monotherapy

    Summary
    EudraCT number
    		 2012-001143-46
    Trial protocol
    		 DE  
    Global end of trial date
    10 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2016
    First version publication date
    17 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLAF237ADE08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01649466
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To demonstrate that vildagliptin in addition to glimepiride is superior to Neutrales Protamin Hagedorn (NPH) insulin in addition to glimepiride with respect to the incidence of the combined endpoint, defined as achieving the blood glucose target level of HbA1c <7.0% without any confirmed hypoglycemic event (HE) (defined as blood glucose (BG) measurement <3.9 mmol/L [<71 mg/dL]) and weight gain (defined as increase of at least 3%) in Type II diabetes mellitus (T2DM) patients. 2. To demonstrate that vildagliptin in addition to glimepiride is superior to NPH insulin in addition to glimepiride with respect to the rate of confirmed HEs (defined as BG measurement <3.9 mmol/L [<71 mg/dL]) in T2DM patients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 Randomized patients were on a stable dose of glimepiride of 4 mg (or if not tolerated, the maximal tolerated dose up to 4 mg) for at least 4 weeks prior to Visit 1. The glimepiride background therapy had to be kept at a stable dose throughout the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 162
    Worldwide total number of subjects
    162
    EEA total number of subjects
    162
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    58
    From 65 to 84 years
    103
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited to participate at 54 sites in Germany.

    Pre-assignment
    Screening details
    		 294 patients were screened over a 1-week period. 162 completed and randomized but 161 got exposed to study drug.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vildagliptin
    Arm description
    		 Subjects received Vildagliptin with glimepiride for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vildagliptin
    Investigational medicinal product code
    Other name
    Galvus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg per os once daily as an add-on to the current glimepiride background therapy. The vildagliptin dose had to be kept stable after randomization (Visit 2) throughout the study.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 4 mg once daily or, if not tolerated, the maximal tolerated dose up to 4 mg.

    Arm title
    		 Neutrales Protamin Hagedorn (NPH) Insulin
    Arm description
    		 Subjects received NPH insulin with glimepiride for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NPH Insulin U100
    Investigational medicinal product code
    Other name
    Protaphane
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 subcutaneous dose per day, forced titration as an add-on to the current glimepiride background therapy. Insulin treatment was to be initiated with a single starting dose of 0.3 – 0.4 U/kg based on glimepiride dosing and BMI (0.3 U/kg, if both glimepiride ≤4 mg and BMI <25 kg/m2, and 0.4 U/kg, if glimepiride ≤4 mg and BMI ≥25 kg/m2). Afterwards, insulin doses were to be titrated individually during the first 4 weeks of treatment using a pre-defined titration regimen in order to achieve a target fasting blood glucose (FBG) concentration of <100 mg/dL (<5.5 mmol/L) without significant hypoglycemia.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 4 mg once daily or, if not tolerated, the maximal tolerated dose up to 4 mg.

    Number of subjects in period 1
    		Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Started
    83
    79
    Completed
    58
    70
    Not completed
    25
    9
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    4
    1
         Protocol violation
    4
    -
         Unsatisfactory therapeutic effect
    14
    2
         Withdrew consent
    1
    4
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vildagliptin
    Reporting group description
    		 Subjects received Vildagliptin with glimepiride for 24 weeks.

    Reporting group title
    Neutrales Protamin Hagedorn (NPH) Insulin
    Reporting group description
    		 Subjects received NPH insulin with glimepiride for 24 weeks.

    Reporting group values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin Total
    Number of subjects
    		 83 79 162
    Age categorical
    Units: Subjects
        ≤65 years
    		 35 30 65
        >65 years
    		 48 49 97
    Gender categorical
    Units: Subjects
        Female
    		 36 31 67
        Male
    		 47 48 95

    End points

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    End points reporting groups
    Reporting group title
    Vildagliptin
    Reporting group description
    		 Subjects received Vildagliptin with glimepiride for 24 weeks.

    Reporting group title
    Neutrales Protamin Hagedorn (NPH) Insulin
    Reporting group description
    		 Subjects received NPH insulin with glimepiride for 24 weeks.

    Primary: Percent of Subjects Reaching Glycosylated Hemoglobin (HbA1c) Below 7.0% Without Confirmed Hypoglycemic Event And Weight Gain

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    End point title
    		 Percent of Subjects Reaching Glycosylated Hemoglobin (HbA1c) Below 7.0% Without Confirmed Hypoglycemic Event And Weight Gain
    End point description
    The percent of subjects achieving the blood glucose target level of HbA1c <7.0% without a hypoglycemic event (HE; defined as blood glucose [BG] measurement <3.9 mmol/L [<71 mg/dL]) and weight gain (defined as increase of at least 3%). HbA1c was monitored at Visits 1 (Screening), 2 (Baseline), 5 (Week 12), and 6 (Week 24). The last available post-baseline HbA1c value was used for the determination of the combined endpoint. Body weight was measured throughout the study at all on-site visits (Visits 1-6). Body weight changes were calculated from the values measured at Visit 2 and Visit 6. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: percent of subjects
        number (not applicable)
    35.4
    34.2
    Statistical analysis title
    		 Analysis of the combined endpoint
    Comparison groups
    Vildagliptin v Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9646
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.985
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.507
         upper limit
    		 1.915

    Primary: Rate of Confirmed Hypoglycemic Events Per Year

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    End point title
    		 Rate of Confirmed Hypoglycemic Events Per Year
    End point description
    Co-primary endpoint is to evaluate the rate of confirmed hypoglycemic events (HEs), defined as a blood glucose (BG) measurement < 3.9mM (71mg/dL). This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: rate of confirmed HEs per year
        arithmetic mean (standard deviation)
    1.3 ( 5.9 )
    5.1 ( 14.7 )
    Statistical analysis title
    		 Analysis of the rate of confirmed HEs
    Comparison groups
    Neutrales Protamin Hagedorn (NPH) Insulin v Vildagliptin
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0164
    Method
    		 Chi-squared
    Parameter type
    		 Rate ratio
    Point estimate
    4.1543
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.299
         upper limit
    		 13.29

    Secondary: Incidence of Severe Hypoglycemic Events

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    End point title
    		 Incidence of Severe Hypoglycemic Events
    End point description
    A severe hypoglycemic event (HE) was defined as a suspected Grade 2 or a confirmed Grade 2 event. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: events
    0
    0
    No statistical analyses for this end point

    Secondary: Rate of Symptomatic Hypoglycemic Events Per Year

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    End point title
    		 Rate of Symptomatic Hypoglycemic Events Per Year
    End point description
    A symptomatic hypoglycemic event (HE) was defined as an HE not necessarily confirmed by laboratory measurement. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: rate of symptomatic HEs per year
        arithmetic mean (standard deviation)
    0.5 ( 2.1 )
    1.8 ( 6.1 )
    No statistical analyses for this end point

    Secondary: Percent of Subjects Who Reached Their Blood Glucose Target Without Any Confirmed Hypoglycemic Event

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    End point title
    		 Percent of Subjects Who Reached Their Blood Glucose Target Without Any Confirmed Hypoglycemic Event
    End point description
    The blood glucose (BG) target was defined as HbA1c below 7.0%. A confirmed hypoglycemic event (HE) was defined as BG measurement <3.9 mmol/L [<71 mg/dL]). This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: percent of subjects
        number (not applicable)
    37.8
    40.5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight at End of Treatment

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    End point title
    		 Change From Baseline in Body Weight at End of Treatment
    End point description
    Body weight was measured throughout the study at all on-site visits (Visits 1-6). Body weight changes were calculated from the values measured at baseline and Week 24 (or end of treatment which is last observation until week 24). A negative value indicates a decrease in weight. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 weeks (or end of treatment i.e. Last post-baseline observation until Week 24)
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    81
    79
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    -0.09 ( 3.6 )
    0.1 ( 4.32 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in HbA1c at End of Treatment

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    End point title
    		 Change From Baseline in HbA1c at End of Treatment
    End point description
    HbA1c was monitored at Visits 1 (Screening), 2 (Baseline), 5 (Week 12), and 6 (Week 24). A negative value indicates a decrease in HbA1c percentage. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24 (or end of treatment i.e. Last post-baseline observation until Week 24 )
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    80
    77
    Units: percent of HbA1c
        arithmetic mean (standard deviation)
    -0.48 ( 0.89 )
    -0.8 ( 0.78 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM-9) Scores at End of Treatment

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    End point title
    		 Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM-9) Scores at End of Treatment
    End point description
    The TSQM-9 is a psychometrically sound and valid measure of the major dimensions of patients' satisfaction with medication. The 4 scales of the original TSQM Version 1.4 with 14 items include the effectiveness scale (questions 1 to 3), the side effects scale (questions 4 to 8), the convenience scale (questions 9 to 11), and the global satisfaction scale (questions 12 to 14). In the TSQM-9, the five items related to side effects of medication are not included. The TSQM-9 domain scores range from 0 to 100, with higher scores representing higher satisfaction on that domain. A positive change from baseline indicates that satisfaction has increased. This endpoint analyzed the Full Analysis Set (FAS), defined as all randomized patients who received at least one dose of randomized study drug, and the Safety Set (SAF), defined as all patients who received at least one dose of study drug whether or not being randomized. The SAF and FAS were identical in this study.
    End point type
    Secondary
    End point timeframe
    24 weeks (or end of treatment i.e. Last post-baseline observation until Week 24)
    End point values
    		 Vildagliptin Neutrales Protamin Hagedorn (NPH) Insulin
    Number of subjects analysed
    82
    79
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Convenience Score (n=61, 70)
    9.6 ( 19.1 )
    -5.6 ( 22 )
        Effectiveness Score (n=61, 70)
    7.1 ( 33.2 )
    7.3 ( 30.3 )
        Global Satisfaction Score (n=61, 69)
    7.7 ( 21.6 )
    4.8 ( 18.9 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Neutrales Protamin Hagedorn (NPH) Insulin
    Reporting group description
    		 Subjects received NPH insulin with glimepiride for 24 weeks.

    Reporting group title
    Vildagliptin
    Reporting group description
    		 Subjects received Vildagliptin with glimepiride for 24 weeks.

    Serious adverse events
    		 Neutrales Protamin Hagedorn (NPH) Insulin Vildagliptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 79 (7.59%)
    11 / 82 (13.41%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    UTERINE CYST
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ALCOHOL POISONING
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    CONGENITAL CYSTIC KIDNEY DISEASE
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONVULSION
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIPLEGIA
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO POSITIONAL
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VERTIGO
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE POLYP
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    GOUTY ARTHRITIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Neutrales Protamin Hagedorn (NPH) Insulin Vildagliptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 79 (51.90%)
    29 / 82 (35.37%)
    Nervous system disorders
    TREMOR
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 82 (2.44%)
         occurrences all number
    10
    7
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 82 (1.22%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 82 (6.10%)
         occurrences all number
    2
    9
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 82 (2.44%)
         occurrences all number
    4
    2
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 79 (10.13%)
    9 / 82 (10.98%)
         occurrences all number
    10
    12
    Metabolism and nutrition disorders
    HYPERGLYCAEMIA
         subjects affected / exposed
    9 / 79 (11.39%)
    10 / 82 (12.20%)
         occurrences all number
    24
    31
    HYPOGLYCAEMIA
         subjects affected / exposed
    23 / 79 (29.11%)
    12 / 82 (14.63%)
         occurrences all number
    140
    44

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2012
    The following changes were made to the study protocol: * Direct bilirubin limits were deleted in exclusion criterion No. 4 in order to be consistent with the current SmPC. Nonetheless, total bilirubin limits were maintained for the ongoing trial. * The confirmation of abnormal liver values within 3 working days (re-test) was included for clarification in exclusion criterion No. 4, since re-testing was previously described in Appendix 2 of the study protocol only.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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